Although significant progress has been made in the development of antifungal drugs, nail fungal infection (e.g., onychomycosis) remains a disease most difficult to treat. The target sites for the treatment of onychomycosis reside in the nail plate, nail bed and nail matrix (see FIG. 1). Topical treatment has not been effective because antifungal drugs cannot readily penetrate the nail plate to reach the infection sites under the nail. Oral administration of antifungal drugs is the only effective way to treat onychomycosis, which has limited the use of some of the more potent antifungal drugs such as itraconazole and ketoconazole because of concern for possible side effects. It has been shown, however, that if the nail barrier can be overcome or eliminated, topical antifungal drug treatment can be effective. For example, both miconazole and ketoconazole were demonstrated to be effective in topically treating onychomycosis after nail avulsion. There is a need for a methodology for topical nail fungal treatment that does not require removal of the nail. Such topical treatment would then permit the use of the more potent antifungal drugs in the treatment of fungal-infected nails.
The nail plate is too thick and too dense for drugs to penetrate at a practical rate. Although nail is similar to stratum corneum of the skin in that it is derived from epidermis, it is mainly composed of hard keratin (highly disulfide-linked) and is approximately 100-fold thicker than stratum corneum. In order to deliver a sufficient amount of drug into the nail plate, the permeability of the nail plate to the drug needs to be enhanced. The permeation-related properties of the nail differ from those observed in stratum corneum primarily in three respects: (a) the total lipid content of the nail is much less than the lipid content of stratum corneum; (b) the nail has a high sulphur content (cystine) in its hard keratin domain whereas the stratum corneum does not; (c) under average conditions, the nail contains much less water than the stratum corneum.
The chemical composition of nail and experimental evidence indicate that the aqueous pathway plays a dominant role in drug penetration into nail. Water is the principal plasticizer for the nail. Upon being hydrated, hard nail plates become softer and more flexible. Nail hydration is influenced by many factors, such as solution pH and certain chemicals. Keratolytic agents, such as urea and salicylic acid are often used to soften nail plates. Urea and a combination of urea and salicylic acid were reported to be used for nonsurgical avulsion of nail dystrophies in clinical studies prior to topical treatment of onychomycosis with satisfactory results.
Nail plates have high sulphur content in the form of disulfide bonds. Certain reducing agents, e.g., cysteine or a derivative thereof, can break the disulfide bond in keratin to increase the ability of the nail to hydrate. The chemical reaction that occurs between the disulfide bonds in nail keratin and a thiol-containing compound (in this case, cysteine) is shown in the following scheme: ##STR1##
This invention provides a delivery means for topical treatment of fungal diseases of the nail which delivers an effective dose of drug to (a) the diseased nail plate (and consequently, the underlying nail bed), of which the hydration capability has been significantly increased to enhance drug permeability (nail route); and (b) the surrounding skin tissues, including nail bed and matrix via the eponychium and hyponychium (skin route--see FIG. 1).